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首页> 外文期刊>Free Radical Biology and Medicine: The Official Journal of the Oxygen Society >Folic acid reverses nitric oxide synthase uncoupling and prevents cardiac dysfunction in insulin resistance: Role of Ca2+/calmodulin-activated protein kinase II
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Folic acid reverses nitric oxide synthase uncoupling and prevents cardiac dysfunction in insulin resistance: Role of Ca2+/calmodulin-activated protein kinase II

机译：叶酸逆转一氧化氮合酶的解偶联并预防胰岛素抵抗中的心脏功能障碍：Ca2 + /钙调蛋白激活的蛋白激酶II的作用

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摘要

Nitric oxide synthase (NOS) may be uncoupled to produce superoxide rather than nitric oxide (NO) under pathological conditions such as diabetes mellitus and insulin resistance, leading to cardiac contractile anomalies. Nonetheless, the role of NOS uncoupling in insulin resistance-induced cardiac dysfunction remains elusive. Given that folic acid may produce beneficial effects for cardiac insufficiency partially through its NOS recoupling capacity, this study was designed to evaluate the effect of folic acid on insulin resistance-induced cardiac contractile dysfunction in a sucrose-induced insulin resistance model. Mice were fed a sucrose or starch diet for 8 weeks before administration of folic acid in drinking water for an additional 4 weeks. Cardiomyocyte contractile and Ca2+ transient properties were evaluated and myocardial function was assessed using echocardiography. Our results revealed whole body insulin resistance after sucrose feeding associated with diminished NO production, elevated peroxynitrite (ONOO-) levels, and impaired echocardiographic and cardiomyocyte function along with a leaky ryanodine receptor (RYR) and intracellular Ca2+ handling derangement. Western blot analysis showed that insulin resistance significantly promoted Ca 2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation, which might be responsible for the leaky RYR and cardiac mechanical dysfunction. NOS recoupling using folic acid reversed insulin resistance-induced changes in NO and ONOO-, CaMKII phosphorylation, and cardiac mechanical abnormalities. Taken together, these data demonstrated that treatment with folic acid may reverse cardiac contractile and intracellular Ca2+ anomalies through ablation of CaMKII phosphorylation and RYR Ca2+ leak.
机译：在诸如糖尿病和胰岛素抵抗等病理状况下，一氧化氮合酶（NOS）可能解偶联以产生超氧化物而不是一氧化氮（NO），从而导致心脏收缩异常。然而，在胰岛素抵抗引起的心脏功能障碍中，NOS解偶联的作用仍然难以捉摸。鉴于叶酸可能部分通过其NOS偶联能力对心脏功能不全产生有益作用，因此本研究旨在评估蔗糖诱导的胰岛素抵抗模型中叶酸对胰岛素抵抗诱导的心脏收缩功能障碍的影响。给小鼠喂食蔗糖或淀粉饮食8周，然后再在饮用水中施用叶酸4周。使用超声心动图评估心肌收缩力和Ca2 +瞬时特性，评估心肌功能。我们的研究结果表明，蔗糖喂养后的全身胰岛素抵抗与NO生成减少，过氧亚硝酸盐（ONOO-）水平升高，超声心动图和心肌细胞功能受损，以及漏液的ryanodine受体（RYR）和细胞内Ca2 +处理紊乱有关。 Western blot分析表明，胰岛素抵抗显着促进了Ca 2 + /钙调蛋白依赖性蛋白激酶II（CaMKII）的磷酸化，这可能是RYR漏出和心脏机械功能障碍的原因。使用叶酸的NOS偶联逆转了胰岛素抵抗引起的NO和ONOO-，CaMKII磷酸化以及心脏机械异常的变化。综上所述，这些数据表明叶酸治疗可通过消融CaMKII磷酸化和RYR Ca2 +泄漏来逆转心脏收缩和细胞内Ca2 +异常。

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